Periodontology 2000, Vol. 33, 2003, 3653 Printed in Denmark.

All rights reserved

Copyright # Blackwell Munksgaard 2003

PERIODONTOLOGY 2000
ISSN 0906-6713

Bone augmentation by means of barrier membranes

mmerle & Ronald E. Jung Christoph H. F. Ha
The development of guided bone regeneration (GBR) has substantially inuenced the possibilities for using implants. The use of bone augmentation procedures has extended the use of endosseous implants to jaw bone areas with insufcient bone volume. Lack of bone volume may be due to congenital, post-traumatic, or post-surgical defects or the result of disease processes. The recently achieved predictability and success of this procedure can change the treatment of a compromised patient into a nearly normal challenge. Based on pioneer experiments investigating healing of periodontal tissues following surgical therapy, a principle of tissue healing was discovered by Nyman & Karring in the early 1980s (60, 62, 87, 88). It was found that cells which have access to and migrate into a given wound space determine the type of tissue regenerating in that space. Both the exclusion of undesired cells from the wound area and the formation of a wound space into which desired cells are allowed to migrate were initially achieved by the placement of barrier membranes (61). The present understanding of the mechanisms leading to regeneration of desired tissues is still in accordance with these initial concepts. The aim of the present chapter was to review the techniques and membrane materials applied for GBR in conjunction with implant based oral rehabilitation. polyurethane, polyhydroxybutyrate, calcium sulfate, micro titanium mesh, and titanium foils. Devices used for GBR in conjunction with endosseous implants should be safe and effective. Since no lifethreatening diseases or deciencies are treated, possible adverse effects emerging from the implanted devices should be kept to a minimum. At the same time, documentation of the effectiveness of the procedures and materials should be available. Certain critical criteria regarding membranes used for guided tissue regeneration have been postulated (47): biocompatibility, cell occlusiveness, integration by the host tissues, clinical manageability, and the space making function. For bioresorbable and biodegradable membranes, additional criteria need to be fullled. Tissue reactions resulting from the resorption of the membrane should be minimal, these reactions should be reversible, and they should not negatively inuence regeneration of the desired tissues (38). Although GBR is a quite successful procedure, a better understanding of the factors critical for success or failure is mandatory. This understanding will lead to more rened clinical protocols and to the manufacture of membrane materials with improved performance for a given indication. Some of these factors include the ideal size of membrane perforations, membrane stability, duration of barrier function, enhanced access of bone and bone-marrow-derived cells to the area for regeneration, ample blood ll of the space, and prevention of soft tissue dehiscence.

Types of membranes
General aspects
A wide range of membrane materials have been used in experimental and clinical studies to achieve GBR including polytetrauoroethylene (PTFE), expanded PTFE (ePTFE), collagen, freeze-dried fascia lata, freeze-dried dura mater allografts, polyglactin 910, polylactic acid, polyglycolic acid, polyorthoester,

Non-resorbable membranes
Polytetrafluoroethylene

With the presentation of the rst successful GBR procedures and the subsequent wide and successful application of ePTFE membranes, this material became a standard for bone regeneration. Expanded PTFE is characterized as a polymer with high stability

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in biological systems. It resists breakdown by host tissues and by microbes and does not elicit immunologic reactions. A frequent complication with membrane application in conjunction with implants is membrane exposure and infection (98). Wound dehiscence and membrane exposure have been reported to impair the amount of bone regenerated in a number of experimental animal (36, 63, 68) and clinical investigations (13, 34, 44, 106). Many of the factors critical for successful bone formation were identied in experimental studies applying ePTFE membranes. Furthermore, clinical protocols regarding surgical procedures, postoperative care and the healing times required were established using non-resorbable membranes. Today, as evidence of the effectiveness of bioresorbable membranes increases, non-resorbable membranes are losing importance in clinical practice and their use is increasingly limited to specic indications. Since the use of ePTFE membranes have been documented to result in successful GBR therapy, results obtained using new materials should always be compared with results of ePTFE membranes.
Titanium-reinforced ePTFE

In situations where bone formation is desired in large defects or in supracrestal areas, conventional ePTFE membranes do not adequately maintain space unless supported by grafting materials. The alternative approach involves the use of membranes with a stable form, such as titanium-reinforced membranes. Titanium-reinforced membranes consist of a double layer of ePTFE with a titanium framework interposed (57, 110, 114). Recent research has demonstrated the successful use of these membranes in vertical ridge augmentation and in the treatment of large defects in the alveolar process.

Bioresorbable membranes
An obvious disadvantage of ePTFE materials is that they are non-resorbable and therefore have to be removed during a second surgical procedure. With regard to patient morbidity and psychological stress, risk of tissue damage, and cost versus benets, the replacement of non-resorbable by bioresorbable membranes is highly desirable. Hence, recent experimental research in GBR has aimed at developing bioresorbable barrier membranes for application in the clinic (Fig. 1). Apart from the fact that the surgical intervention for removal of the membrane is omitted, bioresorb-

able membranes offer some additional advantages (Table 1). Among these are improved soft tissue healing, the incorporation of the membranes by the host tissues (depending on material properties), and a quick resorption in case of exposure, thus eliminating open microstructures prone to bacterial contamination (72, 130). In general, soft tissue healing is improved in the presence of bioresorbable compared to non-resorbable membranes (69, 70, 130). However, some investigators have reported contrasting ndings (72). With ePTFE membranes, 22% (GTAM) and 47% (TRGTAM) of sites showed dehiscences, while 50% of sites treated with a bioresorbable membrane (selfreinforced polyglycolic acid) became dehiscent (72). The average gain of bone was decreased in cases with dehiscences compared to an uneventful submerged regeneration period. Both in the presence and in the absence of soft tissue problems the amount of bone ll of the defects was greater with the ePTFE membranes. Several studies have compared bioresorbable membranes to non-resorbable membranes made of ePTFE. In situations where no membrane exposures were noted, the results regarding the relative amount of bone formation were usually more favorable using the ePTFE membranes compared to the bioresorbable ones (55, 81, 83, 109). Various reasons for the generally lower defect ll with bioresorbable membranes as compared to ePTFE membranes include:  the better space-making capacity of ePTFE;  controlled time of barrier function;  lack of a resorption process and lack of the generation of resorption products that negatively affect bone formation;  longer experience with ePTFE membranes resulting in surgical protocols better tailored for their use. In summary, it appears that bioresorbable membranes in general allow for more bone regeneration than non-resorbable ePTFE membranes. However, if soft tissue dehiscences can be avoided, the ePTFE membranes allow for slightly more bone regeneration than bioresorbable ones.

Choice of material
Obviously, choice of material is very critical when it comes to bioresorbable membranes for GBR. A variety of bioresorbable and non-resorbable devices for GBR have been evaluated in a recent animal and clinical experiments. Depending on the material, inammatory reactions have been documented in

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Fig. 1. a) Radiographic view of a single tooth gap in the anterior maxilla following extraction of a partially resorbed central incisor. b) A screw implant (ITI1 Dental Implant System, Straumann AG, Waldenburg, Switzerland) has been placed at the location of the right central incisor of the maxilla. A dehiscence defect is visible exposing part of the buccal aspect of the rough surfaced implant body. c) A bioresorbable collagen membrane (Bio-Gide, Geistlich AG, Wolhusen, Switzerland) supported by a deproteinized bovine bone mineral (Bio-Oss, Geistlich)

has been placed in an attempt to augment the bone buccal to the implant, thus integrating the titanium surface. d).At the reentry surgery 6 months later, the initially exposed surface of the implant is completely covered by newly formed bone. The buccal bone plate is of sufcient width to adequately support the soft tissues. e) Radiographic view of the implant following incorporation of the nal reconstruction. Note the excellent height of the crestal bone and the adaptation of the bone to the implant surface.

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Table 1. Characteristics of bioresorbable membranes

Advantages No need for membrane removal surgery Simplified surgical procedure with an implant system with two-stage surgical approach Wider range of surgical techniques possible at abutment connection (which coincides with membrane removal for nonresorbable membranes) Better cost-effectiveness Decreased patient morbidity Disadvantages Uncontrolled duration of barrier function Resorption process possibly interfering with wound healing and bone regeneration Need for membrane supporting material

the tissues adjacent to bioresorbable membranes, ranging from mild (1, 93, 97) to severe (37). Another recent study reported on therapeutic failures using polylactic membranes for bone regeneration at periimplant defects in dogs (98). Soft tissue complications were frequent, and the results did not reveal any improvement over control sites without the use of membranes. Bioresorbable membranes that are commercially available at present are not capable of maintaining adequate space unless the defect morphology is very favorable (77). Even if the membranes initially seem able to maintain space, they generally lose their mechanical strength soon after implantation into the tissues. Only in situations where the bony borders of the defects adequately support the membrane have favorable results been reported. When defects are not space making by themselves, failure of bone regeneration results (82, 126). Therefore, they need to be supported in one way or another. A different approach was taken in experimental studies evaluating a form-stable bioresorbable membrane made of polylactic acid in conjunction with a bone substitute in a rabbit skull model (41, 43, 100). New bone was demonstrated to form underneath the membrane beyond the borders of the former calvarium. On the one hand, this experiment demonstrated that, in principle, stiff, bioresorbable membranes are conducive to bone regeneration and bone neoformation. On the other hand, after the observation period of 4 months, no overt signs of breakdown of the membrane were reported. In many clinical situations a resorption time not extending beyond 612 months is mandatory in order not to lose the advantages of resorbability. Bioresorbable materials that may be used for the fabrication of membranes all belong to the groups of natural or synthetic polymers. The best-known groups of polymers used for medical purposes are

collagen and aliphatic polyesters. Currently tested and used membranes are made of collagen or of polyglycolide and/or polylactide or copolymers thereof (for review see (54)). Convincing results of bone regeneration in animal experiments have been reported for collagen membranes (53, 125). Furthermore, reports of human cases or case series (45) as well as controlled clinical studies (130) have been presented describing the successful use of collagen membranes for GBR at exposed implant surfaces. In two recent experiments, a polylactic acid (PLA) membrane was tested for its ability to increase the bone volume in conjunction with an autogenous bone graft; this was compared to controls that were grafted only (74, 75). Both experiments showed more bone formation when the membranes were applied. These results and results from other investigations (83, 109) demonstrate that soft PLA or polyglycoid acid (PGA) membranes are suitable for GBR procedures in conjunction with autogenic grafts. In contrast, unfavorable results were obtained using a bioresorbable barrier composed of poly (d,l-lactic)-co-trimethylene carbonate (52). Control sites treated with ePTFE showed signicantly better bone regeneration. Generally, only a mild inammatory reaction was found associated with the membranes. Five months following implantation, some of the membranes had only just started to lose their original integrity, while others were completely resorbed. This high variability in resorption kinetics complicates clinical use of the material. Similar unfavorable ndings were documented in another study using the same PLA membrane (98). In summary, animal experiments, human case reports and initial controlled clinical studies demonstrate that bioresorbable collagen, PLA and PGA membranes can be used successfully for bone regeneration at implants with exposed surface areas.

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Types of bone defects

Horizontal bone defects include dehiscence, fenestration and infra bony defects. A large number of animal experiments have demonstrated the successful use of bioresorbable membranes in GBR (7, 24, 43, 64, 74, 75, 76, 97, 99, 100, 104, 125), whereas others have reported failures (28, 37, 72, 98, 123).

Horizontal bone defects

Since the early 1990s, various studies have been published describing the successful clinical employment of bioresorbable PLA and PGA membranes for GBR at exposed implant surfaces (8, 77, 79, 89, 109). In contrast, some investigators have reported a reduced defect ll when applying bioresorbable (60%) compared to non-resorbable (8184%) membranes (72). In one of these studies, 18 implants with exposed surfaces were treated in nine patients (109). In the test sites, bioresorbable membranes of polylactic and polyglycolic acid (PLA/PGA) were used, whereas non-resorbable membranes of ePTFE (GTAM) were applied in the control sites. In addition, autogenic bone was placed to cover the exposed implant threads prior to membrane adaptation. The results at reentry 67 months later revealed a more favorable healing using ePTFE (98% defect ll) compared to the bioresorbable group (89% defect ll). This pattern of increased bone formation resulting from the use of ePTFE membranes compared to PLA/PGA membranes has been demonstrated in a histologic study in humans (108).

Vertical bone defects

The indications for vertical ridge augmentation include situations where the remaining bone height is too small for proper anchorage of oral implants; unfavorable crown to implant ratios and unfavorable esthetic outcomes will result from the lack of remaining hard and soft tissues. Data from animal experiments have clearly demonstrated that growth of bone above the external borders of the skeleton was possible using GBR (43, 64, 65, 74, 78, 100, 101). In a recently presented model system, vertical growth of bone has been studied experimentally in humans (42). Titanium hollow cylinders were placed in the retromolar area of healthy subjects. The regen-

erating tissue was harvested at different time points. The results revealed that up to 12 weeks soft tissue was lling the cylinder space, while increasing amounts of mineralized bone was lling the space at later time points up to 9 months. In the rst attempt to augment bone above the borders of the alveolar crest at titanium implants in dogs, reinforced ePTFE membranes showed a gain of 1.8 mm, standard ePTFE membranes revealed a gain of 1.9 mm, and in the controls without membranes the bone height increased by 0.5 mm (58). No graft materials had been placed. In both membrane groups, about 1 mm of non-mineralized tissue was present between the mineralized bone and the membrane at its highest point. Non-mineralized tissue has been reported in contact with the inner surfaces of membranes in other studies as well (57, 106). In the rst clinical study on vertical ridge augmentation in humans, a titanium-reinforced ePTFE membrane was used to cover implants that were allowed to protrude up to 7 mm above the crest (107). The results after 9 months of submerged healing showed bone formation reaching up to 4 mm above the previous border of the alveolar crest. The remainder of the space between the newly formed bone and the membrane was occupied by nonmineralized tissue. Within the area of the newly formed bone, osseointegration of the implants had occurred as demonstrated by histologic analysis of experimentally retrieved test implants. In another study, six patients were treated with titanium-reinforced membranes and autogenic bone collected in a suction lter (114). Twelve months following membrane placement, an average gain of 5 mm of vertical bone height was measured, reaching up to a maximum of 7 mm. Later studies reported improved amounts of vertical bone gain when using autogenous bone grafts or bone substitute materials in addition to the titaniumreinforced ePTFE membranes (110, 115). The ePTFE/tissue interface has recently been characterized in humans (31). The tissue layer in contact with the membrane was described as non-mineralized, rich in cells and vessels, and containing irregularly distributed collagen bers. According to the investigators, this tissue layer may have developed due to micro movements or broblasts penetrating through the membrane from the covering soft tissue ap. The phenomenon of non-mineralized tissue in contact with membrane surfaces has been reported for bioresorbable materials as well (94, 100). The reasons for this are not fully understood and need clarication. Furthermore, it has been postulated

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that lack of adequate stability of membranes will prevent complete bone formation.

Time frame of implantation

In relation to GBR surgery
In principle, attempts at regenerating bone for improved anchorage of oral implants may be performed in conjunction with the placement of the implants or during a surgical intervention prior to implant placement. The staged approach is primarily chosen in situations with large bone defects. Such situations often do not allow obtaining primary stability of the implants in the prosthetically desired position. Hence, the alveolar ridge is augmented in a rst surgical intervention. After the appropriate time for healing, the implants are then placed into a site of sufcient bone volume.
Staged approach

Experimental research on ridge augmentation using GBR was presented in the early 1990s (103). In a dog model, large defects of the alveolar ridge were surgically prepared both in the mandible and in the maxilla to allow for four different treatment modalities. The defects were treated one of the following ways:  covered with ePTFE membranes;  covered with membranes and grafted with porous hydroxyapatite or with a tissue growth matrix of porous PTFE;  grafted with these same materials but not covered with membranes;  neither grafted nor covered. Morphological and histologic analysis revealed that in sites treated with membranes, with or without the addition of grafts, the entire space between the membrane and the jawbone was lled with bone. In the absence of membranes, bone formation did not occur. More recently, studies in humans and animals have lead to further development and renement of this method. In a clinical study involving 40 partially edentulous patients lateral ridge augmentations were performed prior to implant placement (21). Ridge width at the rst surgical intervention precluded implant placement in prosthetically proper position. Autogenous cortico-cancellous block grafts and particulate bone were used in conjunction with ePTFE membranes for ridge augmentation. At the reentry surgery 9 months later, the bone volume had increased to values sufcient for implant placement

in all cases. The investigators concluded that the combination of autogenous bone grafts and ePTFE membranes rendered predictable success. The effect of barrier membranes on the resorption of bone block grafts has recently been studied in an animal experiment (6). Resorption of the grafted bone occurred to various degrees at sites not covered with ePTFE membranes, whereas at the sites with membranes no loss of graft volume due to resorption was recorded. The necessity for membranes was tested in a prospective randomized clinical study involving 13 patients (3). Patients were either treated with onlay bone grafts alone or additionally covered by ePTFE membranes. The width of the ridges was clinically evaluated immediately following graft placement and at the time of membrane removal 6 months later. In the group with membranes signicantly less resorption had occurred. This controlled clinical study conrms animal experimental data and is in accordance with previous case series reporting the occurrence of pronounced resorption of bone grafts (4, 121, 27). Grafts of autogenous bone have traditionally been used for augmentaion of narrow ridges prior to implant placement. In a recent clinical study a deproteinized bovine bone mineral was applied in conjunction with a bioresorbable collagen membrane (128). Spongiosa granules of 0.251 mm particle size were mixed with sterile saline and tetracycline powder and applied to the defect. The grafting material was subsequently covered with a collagen membrane, which was xed to the adjacent bone by use of titanium pins. Flaps were adapted and sutured for primary healing. After 67 months, reentry surgeries were carried out. Biopsies taken from the augmented sites reveal the grafted particles to be well integrated into the newly formed bone. In another study the sites were augmented with bioactive glass immediately following tooth extraction. Membranes were not used in all cases. An overall success rate of 88.6% was reported for the implants after a mean period of function of 29.2 months. Formation of new bone in association with the grafting particles was histologically documented. These newer studies indicate that provided the appropriate protocols are developed, ridge augmentation without the use of autogenous block grafts could possibly evolve into a standard procedure.
Combined approach

Compared to the staged approach the combined method offers some advantages:

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 decreased patient morbidity due to the fact that only one surgical intervention is necessary;  decreased treatment time since regeneration and implantation are performed at the same time;  decreased costs.

Based on these advantages it has been postulated that the combined approach is to be preferred whenever the clinical situation allows doing so (Fig. 2). One of the key points of discussion regarding combined implantation and regeneration was the

Fig. 2. Preoperative view of a single tooth gap in the anterior maxilla following extraction of a central incisor. (a: occlusal view; b: buccal view). Intraoperative view of a nemark1, Nobel Biocare, screw implant (TiUnite Mk III Bra Gothenburg, Sweden) showing a buccal and oral dehiscence. (c: occlusal view; d: buccal view). The defect site has been grafted with a deproteinized bovine bone mineral (Bio-Oss, Geistlich) and autogenous bone harvested from the surrounding area. A titanium reinforced non-resorbable ePTFE membrane (Gore-Tex TR, W.L. Gore & Associates, Inc., Flagstaff, USA) has been trimmed and shaped to cover the bone substitute materials and the implant. The

membrane has been secured at the buccal aspect by two non-resorbable pins. (e: occlusal view; f: buccal view). Six months after implantation and regeneration, a signicant gain of the buccal contour is discernable. (g: occlusal view; h: buccal view). At membrane removal surgery, the surface of the implant is completely covered with new bone (i). A pronounced gain of bone also in buccal direction is observed following uncovering of the closure screw (j). Radiographic view of the implant with an individualized zirconium oxide abutment screwed onto the implant. Note the close adaptation of the bone at the surface of the implant and the crestal bone level being located coronal to the st thread.

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Fig. 2. continued

question whether or not implant surfaces initially not covered by bone can successfully be osseointegrated by the regenerating bone under GBR. A large number of animal experimental studies have histologically demonstrated that such surfaces are truly osseointegrated during the process of bone regeneration (10, 11, 63, 118). In addition, studies in humans have conrmed the ndings reported

in the animal experiments mentioned above (91, 92, 122).

In relation to tooth extraction

With respect to loss or extraction of teeth, implants may be placed in an immediate, a delayed or a late fashion. The time requirements for immediate

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implant placement are fullled when the implant is placed into an extraction socket during the same surgical intervention as the removal of the tooth to be replaced by the implant. The delayed approach indicates that several weeks, usually up to a maximum of 12 weeks, have passed between tooth extraction and implant placement. In situations where more time elapses between tooth extraction and implant placement the term late implant placement is appropriate. In a recent retrospective study immediate, delayed and late implant placements were compared using survival data as well as clinical and radiographic parameters (119). The survival rate for all groups was above 97% 2 years after implantation. In another investigation, no difference regarding bone ll was found between immediate and delayed implant placement at reentry surgery (130). In this study the defects had been treated by collagen membranes and a deproteinized bovine bone mineral.
Immediate implant placement

Increasing numbers of clinical studies demonstrate that the immediate placement of implant into extraction sockets is a method that renders success rates similar to the ones reported for conventional implant placement. Success rates usually well above 90% have been reported in a large number of studies (14, 16, 18, 33, 35, 102). A problem encountered when placing implants immediately into extraction sockets is a lack of soft tissues for primary healing. This soft tissue decit is due to the area of tissue penetration of the tooth prior to extractions. Hence, in order to obtain primary closure, the buccal ap is often mobilized by vertical and horizontal releasing incisions. However, as a result the soft tissue contours, in particular the level of the mucogingival line, are altered and the esthetic outcome may be hampered. Consequently, techniques have recently been published aimed at facilitating primary ap closure through the placement of pedicle or free grafts (23, 32, 84, 96). Closure of the wound over an immediate implant can successfully be obtained by connective tissue grafts, eliminating the need for excessive mobilization of the buccal ap (23, 32). In addition, this technique increases the amount of keratinized tissue and thus provides better conditions for an optimal esthetic result.
Immediate implants without regeneration

Whereas controlled human studies have demonstrated enhanced bone regeneration when exposed

implant surfaces are treated with barrier membranes (29, 90), other investigators have reported adequate bone formation in extraction sockets without the use of membranes (12, 92, 102, 112, 122). In a prospective controlled human clinical trial, test implants were placed into extraction sockets immediately after tooth extraction (92). Implants were located in the premolar and molar region of maxilla and mandible. The diameter of the experimental implants was chosen with the aim of obtaining as much contact with the socket walls as possible. Thus, the distance from the bone to the implant surface was consistently kept at values smaller than 2 mm. The neck of the implants was located at the level of the alveolar crest. No lling materials or membranes were applied. Control implants were inserted into sites with sufcient bone volume. Primary wound closure was performed at both test and control implants. Six months after implant placement, a second stage surgery was performed and healing caps were inserted. After another 6 months, test and control implants were removed with an appropriate trephine drill. Results of clinical measurements, radiographic assessments of bone levels, histologic analysis of crestal bone levels and surface fraction of the implants in direct bone contact revealed no difference between test and control implants. In only three out of 48 test implants was a crestal zone of connective tissue contact discernible extending 1.52 mm. The investigators concluded that implant placement immediately into extraction sockets leads to tissue integration similar to the one obtained with implants placed into intact alveolar crests provided the gap width is smaller than 2 mm. In a human study treating more demanding defects including dehiscence defects with a mean depth of 7 mm, a deproteinized bovine bone was used to ll the gaps between the implants and the bony walls of the defects (112). Again, no membranes were used to cover the defect areas. Although, defect ll was not as predictable as reported in other studies using membranes (108), the majority of the initial defect area was lled with new bone at the 6-month reentry surgery. Compromised results were associated with exposure and loss of the grafting material. There seems to be some consistent results that a gap width of less than 2 mm between the implant and the socket wall will be lled with bone in the absence of membranes. However, more research is needed to characterize the clinical conditions, where membranes in bone regeneration procedures are not necessary and where they are necessary for predictable success.

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Delayed implantation

Since ap dehiscence and resulting membrane exposure are the most frequent complications using the immediate implantation protocol, differing treatment concepts have been developed. In contrast to immediate implantation following tooth extraction, the delayed approach is aimed at allowing soft tissue healing prior to the surgical intervention. The increased amount of soft tissue present simplies the surgical technique for ap closure. Furthermore, it renders esthetically optimal results more predictable. Since the resorption processes of bone are rather small, the loss in bone volume occurring during the rst 12 weeks will usually not hamper placement of the implant and can be compensated by the planned regeneration procedure. In a recent study a comparison between the frequency of membrane exposures was done between three treatment groups: immediate implantation, delayed implantation, and late implantation (130). The results demonstrated that in particular when using non-resorbable ePTFE membranes, the incidence of membrane exposure was signicantly elevated when using the immediate (60%) as compared to the delayed approach (17%). The late approach, however, was associated with even fewer exposures than the delayed approach. Although still present, these differences were less pronounced when a bioresorbable collagen membrane was used. The disadvantages of the delayed approach include the increased treatment time, the need for an additional surgical intervention, the fact that the excellent bone regenerative potential of the fresh extraction socket can no longer fully be taken advantage of, and the decreased bone volume resulting from the occurring bone resorption during soft tissue healing.
Late implantation

exposure is somewhat smaller when using the late approach compared to the delayed one (130). This difference may have signicant effects since bone formation is generally less favorable when dehiscences occur, compared to situations where the soft tissues remain intact during the entire regeneration period (13, 20, 44, 51, 67, 106, 117, 127). Soft tissue dehiscences represent an important complication during GBR with ePTFE membranes. They range from a minor problem affecting only a few percent of membranes up to a serious complication leading to a high rate of complete treatment failures, impaired results, and suffering for the patient (30, 72, 109, 117, 127, 129). This emphasizes the importance of carefully balancing benets and risks when planning GBR therapy. Based on the reports in the literature, there is general agreement that GBR is a difcult procedure to perform and that the skills and experience of the clinician are a critical factor in the success of treatment. Recently, evidence of lower rates of dehiscences associated with bioresorbable membranes compared to non-resorbable membranes has been presented, further promoting the use of bioresorbable membranes.

Clinical mode of healing

Submerged implants

Late implant placement is performed in situations where teeth have been extracted months before. Clinical experience shows that many implantation procedures can be performed in a standard way without the need for GBR. Such procedures would qualify for the term late implantation. However, the focus of this review lies on treatment using GBR for compromised sites. In situations where the late approach is chosen and the need for GBR is still present, no signicant advantages have been described compared to GBR using the delayed approach. However, it has been reported that the incidence of soft tissue dehiscence and subsequent membrane

In general, when GBR is performed in conjunction with implant placement a submerged mode of healing is attempted. The rationale for attempting a submerged mode of healing includes the prevention of bacterial contamination of the implant and the membrane surfaces by bacteria from the oral cavity. In addition, in esthetically difcult regions an additional soft tissue volume is present at the initiation of the prosthetic procedures, which increases the range of therapeutic possibilities to reach an optimal esthetic result. Finally, a submerged implant has been claimed to be optimally protected from adverse loading forces (2). In contrast, recent studies have demonstrated that successful treatment outcomes may also be obtained when implants are kept in a transmucosal location during bone regeneration and tissue integration (18, 25, 40, 45, 66). Furthermore, histologic data obtained in animal experiments as well as from human specimens demonstrate osseointegration of the previously exposed surface areas (63, 122). In contrast to the submerged approach, transmucosal healing eliminates the surgical intervention

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necessary to obtain access to the implant head for performing the prosthetic procedures.
Transmucosal implants

The technique for transmucosal positioning of implants during GBR procedures was rst described in a clinical report of a series of cases (25). Subsequently, another series of cases using ePTFE membranes for regeneration of bone around implant immediately placed into extraction sockets was presented (66). In this study a treatment regimen including the directions for meticulous plaque control was described involving both mechanical means and chemical agents. The results demonstrated 20 out of 21 implants with complete defect ll with new bone upon membrane removal surgery. In a retrospective controlled study, transmucosal implants with GBR were compared with transmucosal implants that did not need any GBR procedures (18). No differences were found regarding the presence of plaque, the prevalence of bleeding on probing, values for the level of the mucosal margin, or probing depths around the implants. Two recent studies presented a defect ll of 94% when using ePTFE membranes (40) and 86% when using bioresorbable membranes (45) for GBR at transucosal implants. Measurements were taken at the time of implant placement and 6 months later. In summary, although studies on bone regeneration at transmucosal implants are still not very numerous, the available data demonstrate that GBR at transmucosal implants is a successful procedure. Hence, primary closure of the site of implantation and regeneration is not a prerequisite for successful treatment outcomes. However, investigators reporting on the transmucosal technique stress the importance of meticulous plaque control during the regeneration period.

Long-term results
Survival rate of implants placed into sites with regenerated/augmented bone using barrier membranes have been reported to vary between 79% and 100% with the majority of studies indicating more than 90% after at least 1 year of function. Thus, in a number of studies a total of 656 implants treated with GBR yielded survival rates ranging from 97.5% to 100% after a 2-year observation period (19, 29, 73, 80, 86, 73). Three studies reported 5-year data (15, 22, 131). Survival rates were 79.4% for 37 implants with dehiscence/fenestration defects treated with ePTFE mem-

branes (15), 92.6% for 41 implants treated with ePTFE membranes (131), 93.9% for 33 implants in extraction sites treated with ePTFE membranes (15) 95.4% for 112 implants treated with a collagen membrane (131), and 100% for 12 implants treated with e-PTFE membranes (22). In a 5-year prospective controlled study, implants placed into pristine bone were compared with implants associated with bone regeneration (131). No signicant differences were found regarding the cumulative implant survival rates in the three groups: sites augmented with a collagen membrane and a deproteinized bovine bone mineral (95.4%), sites augmented with an e-PTFE membrane and a deproteinized bovine bone mineral (92.6%), and sites without augmentation (97.3%). Another study providing controls reported on 38 implants in seven patients (80). In this study, 21 implants were placed in conjunction with GBR and 17 could be placed into the host bone without the need for regenerative therapy. A polylactic, polyglycolic acid membrane was used in all regenerative procedures. After an average of 25 months following incorporation of xed reconstructions, a 100% survival rate was found for both test and control implants and no signicant difference in marginal bone levels was recorded between the two groups. A multicenter evaluation of implants inserted at the time or after vertical ridge augmentation revealed stable crestal bone levels over a period of 15 years (111). Initially, 123 implants had been placed. At the follow-up examination one implant had been lost, while the remainder could be reexamined. Augmentation had been performed using ePTFE membranes in conjunction with a blood clot, with demineralized freeze-dried bone allografts or with autografts. Stable crestal bone levels were reported in the majority of the implants. Only two implants demonstrated an increased crestal bone loss of 3.5 mm and 4 mm, respectively. The investigators concluded that vertically regenerated bone reacts to implant placement in a manner similar to non-regenerated bone. Although the data are derived from a small number of studies showing an adequate design, survival rates similar to the ones generally reported for implants placed conventionally into sites without the need for bone augmentation have been documented.

Outlook into the future

In recent years, many developments in medicine have been based on a better understanding of

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the development of diseases at the cellular and the molecular level. This is a key step to the development of new strategies and materials in medicine. The strategies in most of the medical disciplines are changing in character from a mechanical to a more biological one. The aim is to come up with more effective techniques that predictably promote the bodys natural ability to regenerate lost tissue instead of using external materials to repair lost tissue. The most intriguing method currently being investigated is the application of polypeptide or natural proteins that regulate wound and tissue regeneration. With the improvements in cellular and molecular technologies to isolate, sequence and produce these molecules, a new eld of therapeutic options will be opened.

Growth and differentiation factors in oral surgery

In the past decade a number of basic science experiments and clinical studies have claried biological mechanisms of several growth and differentiation factors in the regeneration of oral soft and hard tissue (49). Growth and differentiation factors currently believed to contribute to periodontal and alveolar ridge augmentation include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), transforming growth factor beta (TGF-a and -b), broblast growth factor (a- and b-FGF), and bone morphogenetic proteins (BMPs 1-15). Of these, bone morphogenetic protein is the most widely studied in the dental literature. In 1965, Urist discovered the inductive bone capacity of a protein extracts from demineralized bone (116). This protein extract was termed bone morphogenetic protein (BMP). The induction process triggered by BMPs involves chemotaxis, proliferation and differentiation of mesenchymal progenitor cells (124). Recombinant biotechnology has made it possible to characterize at least 15 BMPs and to produce quantities of puried recombinant protein for therapeutic application (39). Recombinant human BMP-2 (rhBMP-2) has been found to exhibit very high osteogenic activity in experimental (26, 46, 48, 105) and clinical studies (17, 46).

carrier material, which serves as a delivery system and as a scaffold for cellular ingrowth (95). Collagen has been extensively studied as a carrier material for growth factors applied to promote bone formation in different kinds of indications (17, 49, 85). Different studies (9) using rhBMP-2 in an absorbable collagen sponge (ACS) for alveolar ridge augmentation gained only small amounts of bone. The investigators concluded that the compromised results were due to the failure of the ACS to adequately support the supra-alveolar wound space. In order to overcome this lack of structural strength, rhBMP-2/ACS has been combined with hydroxyapatite in an experiment attempting lateral ridge augmentation (9). In contrast to rhBMP-2/ACS alone, a significant clinical improvement in ridge width was observed with the addition of HA to rhBMP-2/ACS. However, the hydroxyapatite particles were largely encapsulated by brous tissue and they appeared to partially obstruct bone formation. The investigators concluded that space maintenance in BMPinduced bone formation is an important factor (9). Previous animal studies indicated that a xenogenic bone substitute mineral performed well as carrier material for osteoinductive proteins (105, 113). A recent study demonstrated that the results of GBR procedures in human could be improved by the addition of rhBMP-2 to a xenogenic bone substitute mineral. This improvement was documented by a higher degree of bone maturation and an increased graft to bone contact fraction at the BMP-treated sites (59) (Fig. 3). In addition, the xenogenic bone substitute mineral has some therapeutic advantages over HA due to its three-dimensional structure and its resorbability (56). Synthetic polymers, on the other hand, offer possibilities for being combined with biologic factors. Synthetic polymers can reproducibly be fabricated and the growth factors can be incorporated under controlled manufacturing conditions (120). However, the ideal carrier material, which is easy to apply, able to provide space for regeneration, bioresorbable, and allows controlled release of the bioactive molecules has not yet been discovered. Further research is needed to determine the ideal combination of factors for regeneration, the best delivery system, and the optimum doses.

Local delivery of molecules

The regenerative potential of growth and differentiation factors depends upon the carrier material (50, 105). The effect of such proteins is dependent upon a

Membranes
The benet of using both barrier membranes and BMP for bone augmentation remains controversial (26, 49, 59, 71). In a recent study it was found that

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the absence of membranes has not been answered conclusively yet. On the one hand, it is reasonable to apply them as adjunctive agents to GBR therapy to accelerate the membrane-guided bone regeneration. On the other hand, it may be hypothesized that their mode of action is best taken advantage of when membranes are not simultaneously applied, thus allowing all inducible cells from the wound environment access to the area to be regenerated.

Developments in bone augmentation procedures

Further developments in bone augmentation procedures can be related either to simplication of the clinical handling or to inuencing of biological processes. To simplify clinical handling, new materials should comprise a matrix with optimal cell ingrowth capacities and good mechanical properties, providing space for tissue regeneration. No membrane and no specic procedures for mechanical xation should be necessary. This would reduce the technique sensitivity and increase the predictability of bone augmentation. From a biological point of view the growth and differentiation factors may induce earlier bone growth into the area to be regenerated. Thus, the area of regeneration would be stabilized at an earlier time point. Furthermore, the use of such materials would allow treatment of extended bone defect volumes. At present, large bone defects are regularly augmented with autogenous block grafts and membranes (5). The use of synthetic materials would result in lower surgical risks and lower morbidity in augmentation procedures and would represent an important step forward in simplifying bone regeneration techniques.

Fig. 3. Histologic section of a site treated with Bio-Oss and rhBMP-2 (a) showing a signicantly higher surface fraction of the bone substitute particles in direct contact with newly formed bone compared to a site treated with Bio-Oss alone (b). Lamellar bone (lb); woven bone (wb); non-mineralized tissue (nt), bone substitute particles (bo). (Original magnication 100; toluidine blue stain).

non-resorbable ePTFE membrane initially inhibited bone formation with rhBMP-2 (4 weeks) but not at later time points (12 weeks) (26). It has been shown that bone induction by rhBMP-2 occurs at early time points and that rhBMP-2 undergoes rapid clearance. Hence, the use of a membrane may potentially reduce the bone-forming effect of rhBMP-2 due to limited availability of inducible cells. Another animal study in rats reported no difference in bone healing with the combination of rhBMP-2 and an ePTFE membrane compared to rhBMP-2 alone (71). From a clinical point of view, the use of a membrane simplies the handling and the stabilization of the bone substitute mineral at the time of bone augmentation, but from a biological point of view the use of a membrane may block the recruitment of cells from the environment. The question whether or not bioactive molecules are best used in conjunction with membranes or in

Conclusions
 Presently available data demonstrate GBR therapy to be a predictable and successful procedure to augment bone in a horizontal direction at sites exhibiting insufcient bone volume for implant placement under standard conditions.  Although data are not plentiful, vertical augmentation using this technique has successfully been performed by various groups of investigators.  An increasing body of literature demonstrates bioresorbable membranes to render success rates similar to the ones obtained with non-resorbable membranes for the treatment of horizontal defects.

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 Some studies indicate that implant placement immediately following tooth extraction without the use of membranes may lead to complete bone regeneration of the gap between the implant and the socket wall, provided this gap does not surpass a certain distance.  A few long-term studies indicate that the survival rate of implants partly resting in augmented bone is similar to implants placed in native bone.  It is expected that bone regeneration using growth and differentiation factors will play an important role in the future.  The literature on GBR for implant placement is mostly limited to compromised sites and studies evaluating this procedure in compromised patients are not available.

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